Objective: To determine if focal ‘nuclear atypia’ or ‘microfollicular architecture’ portends a higher risk of malignancy than other subcategories of atypia of undetermined significance (AUS) in thyroid fine-needle aspirations (FNAs). Study Design: The frequencies of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories were calculated from 3,956 thyroid FNAs interpreted over a 26-month period at The Johns Hopkins Hospital after adoption of TBSRTC. TBSRTC criteria were applied strictly. The risk of malignancy, specifically for AUS subcategories, was analyzed by cyto-histo correlation. Results: Of the 133 cases diagnosed as AUS, 32% were found to have stageable carcinoma (not incidental microcarcinoma) on resection. When the subset of AUS with ‘nuclear atypia’ (AUS-N) was separated from other AUS cases, 48% (30/62) of them had stageable carcinoma on resection; of the AUS subset with ‘microfollicular architecture’ (AUS-F), 27% (8/30) were malignant on resection. The ‘suspicious for papillary thyroid carcinoma’ (SPTC) group maintained a higher risk of malignancy versus AUS-N (relative risk, RR 1.57; 95% CI 1.23–1.81). Conclusion: The subcategory of ‘nuclear atypia’ within AUS indicates a higher risk of malignancy than other subcategories of AUS but has a lower risk of malignancy than SPTC does. Thus, it is an important distinction with potential clinical implications.

Wong CK, Wheeler MH: Thyroid nodules: rational management. World J Surg 2000;24:934–941.
Hamberger B, Gharib H, Melton LJ, Goellner JR, Zinsmeister AR: Fine-needle aspiration biopsy of thyroid nodules: impact on thyroid practice and cost of care. Am J Med 1982;73:381–384.
Ross DS: Editorial: predicting thyroid malignancy. J Clin Endocrinol Metab 2006;91:4253–4255.
Sipos JA, Mazzaferri EL: Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol) 2010;22:395–404.
Mazzaferri EL: Managing small thyroid cancers. JAMA 2006;295:2179–2182.
Chen AY, Jemal A, Ward EM: Increasing incidence of differentiated thyroid cancer in the united states, 1988–2005. Cancer 2009;115:3801–3807.
Davies L, Ouellette M, Hunter M, Welch HG: The increasing incidence of small thyroid cancers: where are the cases coming from? Laryngoscope 2010;120:2446–2451.
Davies L, Welch HG: Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 2006;295:2164–2167.
Lewis CM, Chang KP, Pitman M, Faquin WC, Randolph GW: Thyroid fine-needle aspiration biopsy: variability in reporting. Thyroid 2009;19:717–723.
Cibas ES, Sanchez MA: The National Cancer Institute Thyroid Fine-Needle Aspiration State-of-the-Science Conference: inspiration for a uniform terminology linked to management guidelines. Cancer 2008;114:71–73.
Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, Vielh P, DeMay RM, Sidawy MK, Frable WJ: Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425–437.
Baloch ZW, Cibas ES, Clark DP, Layfield LJ, Ljung BM, Pitman MB, Abati A: The National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference: a summation. Cytojournal 2008;5:6.
Cibas ES, Ali SZ, NCI Thyroid FNA State of the Science Conference: The Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol 2009;132:658–665.
Cibas ES, Ali SZ: The Bethesda System for Reporting Thyroid Cytopathology. Thyroid 2009;19:1159–1165.
Ali SZ, Cibas ES: The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes. New York, Springer, 2009.
Nayar R, Ivanovic M: The indeterminate thyroid fine-needle aspiration: experience from an academic center using terminology similar to that proposed in the 2007 National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Cancer 2009;117:195–202.
Somma J, Schlecht NF, Fink D, Khader SN, Smith RV, Cajigas A: Thyroid fine needle aspiration cytology: follicular lesions and the gray zone. Acta Cytol 2010;54:123–131.
Layfield LJ, Morton MJ, Cramer HM, Hirschowitz S: Implications of the proposed thyroid fine-needle aspiration category of ‘follicular lesion of undetermined significance’: a five-year multi-institutional analysis. Diagn Cytopathol 2009;37:710–714.
Renshaw AA: Subclassification of atypical cells of undetermined significance in direct smears of fine-needle aspirations of the thyroid: distinct patterns and associated risk of malignancy. Cancer Cytopathol 2011;119:322–327.
Goldstein RE, Netterville JL, Burkey B, Johnson JE: Implications of follicular neoplasms, atypia, and lesions suspicious for malignancy diagnosed by fine-needle aspiration of thyroid nodules. Ann Surg 2002;235:656–662, discussion 662–654.
Jing X, Knoepp SM, Roh MH, Hookim K, Placido J, Davenport R, Rasche R, Michael CW: Group consensus review minimizes the diagnosis of ‘follicular lesion of undetermined significance’ and improves cytohistologic concordance. Diagn Cytopathol 2011, DOI: 10.1002/dc.21702.
Ohori NP, Nikiforova MN, Schoedel KE, LeBeau SO, Hodak SP, Seethala RR, Carty SE, Ogilvie JB, Yip L, Nikiforov YE: Contribution of molecular testing to thyroid fine-needle aspiration cytology of ‘follicular lesion of undetermined significance/atypia of undetermined significance’. Cancer Cytopathol 2010;118:17–23.
Melillo RM, Santoro M, Vecchio G: Differential diagnosis of thyroid nodules using fine-needle aspiration cytology and oncogene mutation screening: are we ready? F1000 Med Rep 2010;2:62.
Chudova D, Wilde JI, Wang ET, Wang H, Rabbee N, Egidio CM, Reynolds J, Tom E, Pagan M, Rigl CT, Friedman L, Wang CC, Lanman RB, Zeiger M, Kebebew E, Rosai J, Fellegara G, LiVolsi VA, Kennedy GC: Molecular classification of thyroid nodules using high-dimensionality genomic data. J Clin Endocrinol Metab 2010;95:5296–5304.
Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, Zeiger MA, Westra WH, Wang Y, Khanafshar E, Fellegara G, Rosai J, Livolsi V, Lanman RB: A large multicenter correlation study of thyroid nodule cytopathology and histopathology. Thyroid 2011;21:243–251.
Bartolazzi A, Orlandi F, Saggiorato E, Volante M, Arecco F, Rossetto R, Palestini N, Ghigo E, Papotti M, Bussolati G, Martegani MP, Pantellini F, Carpi A, Giovagnoli MR, Monti S, Toscano V, Sciacchitano S, Pennelli GM, Mian C, Pelizzo MR, Rugge M, Troncone G, Palombini L, Chiappetta G, Botti G, Vecchione A, Bellocco R, Italian Thyroid Cancer Study Group (ITCSG): Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study. Lancet Oncol 2008;9:543–549.
Coli A, Bigotti G, Zucchetti F, Negro F, Massi G: Galectin-3, a marker of well-differentiated thyroid carcinoma, is expressed in thyroid nodules with cytological atypia. Histopathology 2002;40:80–87.
Banks ND, Kowalski J, Tsai HL, Somervell H, Tufano R, Dackiw AP, Marohn MR, Clark DP, Umbricht CB, Zeiger MA: A diagnostic predictor model for indeterminate or suspicious thyroid FNA samples. Thyroid 2008;18:933–941.
Jo VY, Stelow EB, Dustin SM, Hanley KZ: Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol 2010;134:450–456.
Vanderlaan PA, Marqusee E, Krane JF: Clinical outcome for atypia of undetermined significance in thyroid fine-needle aspirations: should repeated FNA be the preferred initial approach? Am J Clin Pathol 2011;135:770–775.
Theoharis CG, Schofield KM, Hammers L, Udelsman R, Chhieng DC: The Bethesda thyroid fine-needle aspiration classification system: year 1 at an academic institution. Thyroid 2009;19:1215–1223.
Faquin WC, Baloch ZW: Fine-needle aspiration of follicular patterned lesions of the thyroid: diagnosis, management, and follow- up according to National Cancer Institute (NCI) recommendations. Diagn Cytopathol 2010;38:731–739.
Renshaw AA: Should ‘atypical follicular cells’ in thyroid fine-needle aspirates be subclassified? Cancer Cytopathol 2010;118:186–189.
Roh MH, Jo VY, Stelow EB, Faquin WC, Zou KH, Alexander EK, Larsen PR, Marqusee E, Benson CB, Frates MC, Gawande A, Moore FD, Cibas ES: The predictive value of the fine-needle aspiration diagnosis ‘suspicious for a follicular neoplasm, Hürthle cell type’ in patients with Hashimoto thyroiditis. Am J Clin Pathol 2011;135:139–145.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.